Hypoosmotic compositions comprising a polymer and a complexed contrast agent for MRI

ABSTRACT

Novel contrast media for use in magnetic resonance imaging are described. Such contrast media are comprised of biocompatible polymers either alone or in admixture with one or more contrast agents such as paramagnetic, superparamagnetic or proton density contrast agents. Additionally, the polymers or polymer and contrast agent admixtures may be mixed with one or more biocompatible gases to increase the relaxivity of the resultant preparation, and/or with other components. In a preferable embodiment, the contrast medium is hypoosmotic.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. Ser. No. 08/251,484, filed May31, 1994, which in turn is a divisional of U.S. Ser. No. 07/960,591,filed Oct. 13, 1992 now U.S. Pat. No. 5,368,840, which in turn is acontinuation-in-part of U.S. Ser. No. 07/507,125, filed Apr. 10, 1990now abandoned, the disclosures of which are incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the field of magnetic resonance imaging, morespecifically to the use of polymers or polymers in combination withcontrast agents and/or gases as contrast media for magnetic resonanceimaging.

2. Description of the Prior Art

There are a variety of imaging techniques that have been used todiagnose disease in humans. One of the first imaging techniques employedwas X-rays. In X-rays, the images produced of the patients' body reflectthe different densities of body structures. To improve the diagnosticutility of this imaging technique, contrast agents are employed toincrease the density between various structures, such as between thegastrointestinal tract and its surrounding tissues. Barium and iodinatedcontrast media, for example, are used extensively for X-raygastrointestinal studies to visualize the esophagus, stomach, intestinesand rectum. Likewise, these contrast agents are used for X-ray computedtomographic studies to improve visualization of the gastrointestinaltract and to provide, for example, a contrast between the tract and thestructures adjacent to it, such as the vessels or lymph nodes. Suchgastrointestinal contrast agents permit one to increase the densityinside the esophagus, stomach, intestines and rectum, and allowdifferentiation of the gastrointestinal system from surroundingstructures.

Magnetic resonance imaging (MRI) is a relatively new imaging techniquewhich, unlike X-rays, does not utilize ionizing radiation. Like computedtomography, MRI can make cross-sectional images of the body, however MRIhas the additional advantage of being able to make images in any scanplane (i.e., axial, coronal, sagittal or orthogonal). Unfortunately, thefull utility of MRI as a diagnostic modality for the body, particularlyin the abdominal and pelvic region, is hampered by the lack of aneffective gastrointestinal contrast agent. Without such an agent, it isoften difficult using MRI to differentiate the intestines from, forexample, adjacent soft tissues and lymph nodes. If better contrastagents were available, the overall usefulness of MRI as an imaging agentwould improve, and the diagnostic accuracy of this modality in thegastrointestinal region would be greatly enhanced.

MRI employs a magnetic field, radiofrequency energy and magnetic fieldgradients to make images of the body. The contrast or signal intensitydifferences between tissues mainly reflect the T1 and T2 relaxationvalues and the proton density (effectively, the free water content) ofthe tissues. In changing the signal intensity in a region of a patientby the use of a contrast medium, several possible approaches areavailable. For example, a contrast medium could be designed to changeeither the T1, the T2 of the proton density.

A paramagnetic contrast agent such as Gd-DTPA causes longitudinalrelaxation to shorten T1. This increases the signal intensity onT1-weighted images. A superparamagnetic contrast agent such as ferritesworks predominantly on transverse relaxation causing a shortening of T2and decreasing signal intensity on T2-weighted images. A contrast agentcould also work by altering the proton density, specifically bydecreasing the amount of free water available that gives rise to thesignal intensity.

Agents that increase the signal intensity from the lumen compared to thenative contents are termed positive contrast agents. A number of thesehave been examined as contrast agents for MRI. These include fats andoils (Newhouse et al., Radiology, 142(P): 246 (1982)), which increasesignal as a result of their short T1, long T2 and high intrinsic protondensity, as well as various paramagnetic agents that increase signal bydecreasing the T1 of water protons. Examples of such paramagnetic agentsinclude Gd-DTPA (Kornmesser et al., Magn. Reson. Imaging, 6: 124 (1988),and Laniado et al., AJR, 150: 817 (1988)), Gd-DOTA (Hahn et al. Magn.Reson. Imaging, 6: 78 (1988)), Gd-oxalate (Runge, V. M. et al.,Radiology, 147: 789 (1983)), Cr-EDTA (Runge, V. M. et al., Physiol.Chem. Phys. Med. NMR, 16: 113 (1984)), Cr-Tris-acetylacetonate (Clantonet al., Radiology, 149: 238 (1983)), ferric chloride (Young et al., CT,5: 543 (1981)), ferrous gluconate (Clanton et al., Radiology, 153: 159(1984)), ferric ammonium citrate and ferrous sulfate (Wesbey et al.,Radiology, 149: 175 (1983) and Tscholakoff et al., AJR, 148: 703 (1987))as well as iron complexes (Wesbey et al., Magn. Reson. Imaging, 3: 57(1985) and Williams et al., Radiology, 161: 315 (1986)).

Alternatively, agents that decrease the signal intensity from the lumenare termed negative contrast agents. Examples include particulate ironoxides (Hahn et al., Radiology, 164: 37 (1987), Widder et al., AJR, 149:839 (1987)) which decrease signal via T2 shortening, as well asgas-evolving materials (Weinreb et al., J. Comput. Assist. Tomogr., 8:835 (1984)) and perfluorocarbons (Mattrey et al., AJR, 148: 1259 (1987))which act through changes in the proton density. It should be recognizedthat all paramagnetic substances at sufficiently high concentrations canalso result in a decrease in signal intensity via T2 shortening.

The existing MRI contrast agents all suffer from a number of limitationswhen employed as oral gastrointestinal agents. Positive contrast agentsincrease the image noise arising from intrinsic peristaltic motions andmotions imposed via respiration or cardiovascular action. Positivecontrast agents such as Gd-DTPA are subject to the further complicationthat the signal intensity depends upon the concentration of the agent aswell as the pulse sequence used. Absorption of contrast agent from thegastrointestinal tract complicates interpretation of the images,particularly in the distal portion of the small intestine, unlesssufficiently high concentrations of the paramagnetic species are used(Kornmesser et al., Magn. Reson. Imaging, 6: 124 (1988)). Negativecontrast agents by comparison are less sensitive to variation in pulsesequence and provide more consistent contrast. However at highconcentrations, particulates such as ferrites can cause magneticsusceptibility artifacts which are particularly evident in the colonwhere the absorption of intestinal fluid occurs and thesuperparamagnetic material may be concentrated. Negative contrast agentstypically exhibit superior contrast to fat, however on T1-weightedimages, positive contrast agents exhibit superior contrast versus normaltissue. Since most pathological tissues exhibit longer T1 and T2 thannormal tissue, they will appear dark on T1-weighted and bright onT2-weighted images. This would indicate that an ideal contrast agentshould appear bright on T1-weighted images and dark on T2-weightedimages. None of the currently available MRI contrast media for use withthe gastrointestinal tract meet these dual criteria.

Toxicity is another problem with the existing contrast agents. With anydrug there is some toxicity, the toxicity generally being dose related.With the ferrites there are often symptoms of nausea after oraladministration, as well as flatulence and a transient rise in serumiron. The paramagnetic contrast agent Gd-DTPA is an organometalliccomplex of gadolinium coupled with the complexing agent diethylenetriamine pentaacetic acid. Without coupling, the free gadolinium ion ishighly toxic. The peculiarities of the gastrointestinal tract, whereinthe stomach secretes acids and the intestines release alkalines, raisethe possibility of decoupling and separation of the free gadolinium fromthe complex as a result of these changes in pH during gastrointestinaluse. Certainly, minimizing the dose of either gastrointestinal contrastagent, whether paramagnetic or superparamagnetic, is important forminimizing any potential toxic effects.

New and/or better contrast agents useful in magnetic resonance imaging,particularly in the imaging of the gastrointestinal tract but also inthe imaging of other regions of the body such as through thevasculature, are needed. The present invention is directed to thisimportant end.

SUMMARY OF THE INVENTION

The present invention is directed to a contrast medium useful formagnetic resonance imaging, said contrast medium comprising an aqueoussolution or suspension of at least one biocompatible polymer.Optionally, the contrast medium further comprises, in admixture,contrast agents, especially paramagnetic, superparamagnetic and/orproton density contrast agents. The polymer or polymer and contrastagent admixtures may also optionally comprise, if desired, biocompatiblegases, preferably gases such as air, oxygen, carbon dioxide, nitrogen,xenon, neon and/or argon, as well as other components as desired.

In a preferable embodiment, the present invention encompasses a contrastmedium for use in magnetic resonance imaging comprising an aqueoussolution or suspension of at least one biocompatible polymer inadmixture with a contrast agent, wherein the contrast medium ishypoosmotic to the bodily fluids of the patient. In further preferableembodiments, the present invention is directed to a contrast mediumcomprising an aqueous solution or suspension of a biocompatiblesynthetic polymer in admixture with a contrast agent, a contrast mediumcomprising an aqueous solution or suspension of a biocompatiblesynthetic non-cross-linked polymer, a contrast medium consistingessentially of an aqueous solution or suspension of a biocompatiblenon-cross-linked polymer, and a contrast medium consisting essentiallyof an aqueous solution or suspension of at least one biocompatiblepolymer and at least one biocompatible gas.

The subject invention also pertains to a method of providing an image ofan internal region of a patient, especially an image of thegastrointestinal region of the patient, said method comprising (i)administering to the patient one or more of the aforementioned contrastmedia, and (ii) scanning the patient using magnetic resonance imaging toobtain visible images of the region.

Further, the present invention encompasses a method for diagnosing thepresence of diseased tissue in a patient, especially in thegastrointestinal region of the patient, said method comprising (i)administering to the patient one or more of the foregoing contrastmedia, and (ii) scanning the patient using magnetic resonance imaging toobtain visible images of any diseased tissue in the region.

These and other aspects of the invention will become more apparent fromthe following detailed description when taken in conjunction with thefollowing drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagrammatic view of a contrast medium in accordance withthe present invention;

FIG. 2 is a graph of relaxation rate (1/sec) versus percent polyethyleneglycol (w/w), wherein the polyethylene glycol polymer is in aqueoussolution both with and without a Gd-DTPA contrast agent;

FIG. 3 is a graph of relaxation rate (1/sec) versus percent dextrose(w/w), wherein the dextrose polymer is in aqueous solution both with andwithout a Gd-DTPA contrast agent;

FIG. 4 is a graph of transverse relation rate 1/T2 (1/sec) versusferrite concentration (micromolar), wherein the ferrite contrast agentis in aqueous solution with and without a cellulose polymer (and whereinthe cellulose polymer is present with and without carbon dioxide gas).

DETAILED DESCRIPTION OF INVENTION

Any of the wide variety of biocompatible (physiologically compatible)polymers known in the art may be employed in the medium or methods ofthe subject invention. As will be readily apparent to those skilled inthe art, there are numerous types of such polymers available.Preferably, the polymer chosen is one which has a relatively high waterbinding capacity. Also preferably, the polymer has limited ability forion complexation. Where imaging of the gastrointestinal region isdesired, preferably the polymer chosen is one which is not substantiallyabsorbed from or degraded within the gastrointestinal region. Thepolymers useful in the present invention can be of either synthetic ornatural origin. As used herein, the term polymer denotes a compoundcomprised of two or more repeating monomeric units, and preferably 10 ormore repeating monomeric units. The polymers may be cross-linked, ifdesired. Preferably, however, the polymers are not cross-linked(referred to herein as non-cross-linked).

Exemplary synthetic polymers suitable for use in the present inventioninclude polyethylenes (such as, for example, polyethylene glycol),polyoxyethylenes (such as, for example, polyoxyethylene glycol),polypropylenes (such as, for example, polypropylene glycol), pluronicacids and alcohols, polyvinyls (such as, for example, polyvinylalcohol), and polyvinylpyrrolidone. Exemplary natural polymers suitablefor use in the present invention include polysaccharides.Polysaccharides include, for example, arabinans, fructans, fucans,galactans, galacturonans, glucans, mannans, xylans (such as, forexample, inulin), levan, fucoidan, carrageenan, galactocarolose, pectin(including high methoxy pectin and low methoxy pectin; with low methoxypectin denoting pectin in which less than 40% of the carboxylic acidgroups are esterified and/or amidated, and high methoxy pectin denotingpectin in which 40% or more of the carboxylic acid groups are esterifiedand/or amidated), pectic acid, amylose, pullulan, glycogen, amylopectin,cellulose, carboxylmethylcellulose, hydroxypropyl methylcellulose,dextran, pustulan, chitin, agarose, keratan, chondroitin, dermatan,hyaluronic acid and alginic acid, and various other homopolymers orheteropolymers such as those containing one or more of the followingaldoses, ketoses, acids or amines: erythrose, threose, ribose,arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose,idose, galactose, talose, erythrulose, ribulose, xylulose, psicose,fructose, sorbose, tagatose, glucuronic acid, gluconic acid, glucaricacid, galacturonic acid, mannuronic acid, guluronic acid, glucosamine,galactosamine and neuraminic acid. It is recognized that some polymersmay be prepared by chemically modifying naturally occurring polymers.Such chemically modified natural polymers are to be considered withinthe scope of the phrase natural polymers, as used herein.

The polymers of the present invention may be employed in various shapesand forms, such as, for example, as fibers, beads, and particles. Thepolymers may also be of varying molecular weights, such as highmolecular weight polymers (that is, equal to or greater than 30,000weight average molecular weight) or low molecular weight polymers (thatis, less than 30,000 weight average molecular weight). For reasons ofdiagnostic efficacy, preferably the polymers are low molecular weightpolymers, more preferably having a molecular weight (weight average) ofabout 25,000 or less, still more preferably less than about 20,000, evenmore preferably less than about 15,000, and most preferably less thanabout 10,000. One highly preferable weight average molecular weightrange is between about 25,000 and about 1,500.

Polyethylene glycol (PEG), a synthetic polymer that exhibits a highwater binding capacity, is particularly preferred for use in the subjectinvention. As a result of their high water binding capacity andconcomitant decrease in the amount of free water in solution, PEG andsimilar polymers serve to alter the proton density in solution.Furthermore, PEG is used for the fractional precipitation of proteinsfrom solution, which is believed to be due to in part to the excludedvolume effects caused by this polymer whereby the protein is excludedfrom regions of the solution occupied by the polymer and is concentratedup in the water spaces, that is, the extrapolymer spaces, between theindividual molecules of the polymer. This exclusion and concentrationeffect is illustrated diagrammatically in FIG. 1, with the polymer beingrepresented by the squiggly lines and the contrast agent beingrepresented by the solid dots. Since PEG exhibits limited ability forion complexation, it will also cause a small paramagnetic chelate suchas Gd-DTPA to be concentrated such that the effective concentration andthe relaxivity of the paramagnetic species will be higher in mixtureswith the polymer than in the absence of the polymer. For these and otherreasons, PEG, and related polymers, are particularly preferred polymersfor the subject invention. PEG, as well as other synthetic polymers, maybe prepared, in varying molecular weights, using conventionalmethodology.

Other natural polymers particularly preferred for reasons of diagnosticefficacy include polygalacturonic acid (and other polyuronic acids, suchas polyglucuronic acid, polymannuronic acid, polyguluronic acid,hyaluronic acid etc.), low methoxy pectin, dextran, and cellulose.Especially preferred is low molecular weight polygalacturonic acid andlow molecular weight low methoxy pectin, especially polygalacturonicacid. Polyuronic acids such as polygalacturonic acid, and low methoxypectin, dextran, cellulose and other such polymers, may be obtained orprepared, in varying molecular weights, using conventional techniques.

The polymers of the present invention may be employed alone, in anaqueous solution or suspension, as a contrast medium for magneticresonance imaging. Alternatively, if desired, the polymers may beemployed in admixture with conventional physiologically compatiblecontrast agents. By admixture, it is meant that the contrast agent issimply added to the polymer-containing medium, and is not chemicallybound to the polymer by a covalent linkage. Electrostatic interactionsor hydrogen bonding may, however, exist between the polymer and contrastagents, and such associations are considered to be within the ambit ofthe term admixture.

Numerous contrast agents are well known to those skilled in the art andinclude, for example, paramagnetic, superparamagnetic and proton densitycontrast agents.

Exemplary paramagnetic contrast agents suitable for use in the subjectinvention include stable free radicals (such as, for example, stablenitroxides), as well as compounds comprising transition, lanthanide andactinide elements which may, if desired, be covalently or noncovalentlybound to complexing agents or to proteinaceous macromolecules.Preferable elements include Gd(III), Mn(II), Cu(II), Cr(III), Fe(II),Fe(III), Co(II), Er(II), Ni(II), Eu(III) and Dy(III). More preferably,the elements include Gd(III), Mn(II), Cu(II), Fe(II), Fe(III), Eu(III)and Dy(III), especially Mn(II) and Gd(III). Preferable complexing agentsinclude, for example, diethylenetriamine-pentaacetic acid (DTPA),ethylene-diaminetetraacetic acid (EDTA),1,4,7,10-tetraazacyclododecane-N,N',N',N'"-tetraacetic acid (DOTA),1,4,7,10-tetraazacyclododecane-N,N',N"-triacetic acid (DO3A),3,6,9-triaza-12-oxa-3,6,9-tricarboxymethylene-10-carboxy-13-phenyl-tridecanoicacid (B-19036), hydroxybenzylethylene-diamine diacetic acid (HBED),N,N'-bis(pyridoxyl-5-phosphate)ethylene diamine, N,N'-diacetate (DPDP),1,4,7-triazacyclononane-N,N'N"-triacetic acid (NOTA),1,4,8,11-tetraazacyclotetradecane-N,N'N",N'"-tetraacetic acid (TETA) andkryptands (that is, macrocyclic complexes). More preferably, thecomplexing agents are DTPA, DOTA, DO3A and kryptands, most preferablyDTPA. Preferable proteinaceous macromolecules include albumin, collagen,polyarginine, polylysine, polyhistidine, γ-globulin and β-globulin. Morepreferably, the proteinaceous macromolecules comprise albumin,polyarginine, polylysine, and polyhistidine. Most preferably, theparamagnetic contrast agents employed in the present invention areMn(II)-DTPA, Mn(II)-DOTA, Mn(II)-DO3A, Mn(II)-kryptands, Gd(III)-DTPA,Gd(III)-DOTA, Gd(III)-DO3A, or Gd(III)-kryptands, especially Mn(II)-DTPAor Gd(III)-DTPA.

Exemplary superparamagnetic contrast agents suitable for use in thesubject invention include ferro- or ferrimagnetic compounds, such aspure iron, magnetic iron oxide (such as magnetite), γ-Fe₂ O₃, manganeseferrite, cobalt ferrite and nickel ferrite. Exemplary proton densitycontrast agents include perfluorocarbons.

The polymer or polymer and contrast agent admixtures of the subjectinvention may also be employed, if desired, in admixture withbiocompatible gases. In the case of both negative and positive contrastagents, such gases often serve to increase the efficacy of the contrastmedium. The gas can be bubbled through the medium using conventionaltechniques. Any biocompatible gas is suitable for use in the presentinvention. Numerous such gases are well known to those skilled in theart. Exemplary biocompatible gases include, air, oxygen, carbon dioxide,nitrogen, xenon, neon and argon, the foregoing list referencing, ofcourse, the most common isotope of such gases.

Wide variations in the amounts of the polymer, and the contrast agentand/or gas, can be employed in the contrast medium of the invention.Preferably, however, the polymer is present in a concentration of atleast about 0.01% to about 1%, by weight, more preferably, between about0.05% and about 50%, by weight, even more preferably between about 0.5%and about 40%, and generally most preferably between about 0.5% andabout 5%, by weight. Of course, as those skilled in the art wouldrecognize, within these parameters the optimum polymer concentrationwill be influenced by the molecular weight of the polymer, its waterbinding capacity, as well as other characteristics of the particularpolymer employed. Also, preferably, in the case of paramagnetic andproton density contrast agents, the contrast agent is present in aconcentration of at least about 0.1 millimolar, more preferably betweenabout 0.5 and about 2 millimolar, most preferably between about 0.7 andabout 1 millimolar. In the case of superparamagnetic agents, theconcentration is preferably at least about 1 micromolar, more preferablybetween about 5 and about 50 micromolar, and most preferably is about 10micromolar. Where gas is employed, preferably at least about 20 psi isbubbled through the solution for about one minute prior toadministration, more preferably between about 30 or about 50 psi, mostpreferably about 40 psi.

If desired, in addition, the contrast medium may further comprise aphysiologically compatible suspending or viscosity increasing agent,referred to herein collectively as a suspending agent. The phrasesuspending agent, as used herein, denotes a compound that assists inproviding relative uniformity or homogeneity to the contrast medium. Anumber of such agents are available, including xanthum gum, acacia,agar, alginic acid, aluminum monostearate, bassorin, karaya, gum arabic,unpurified bentonite, purified bentonite, bentonite magma, carbomer934P, calcium carboxymethylcellulose, sodium carboxymethylcellulose,carboxymethylcellulose sodium 12, carrageenan, cellulose(microcrystalline), dextran, gelatin, guar gum, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium aluminumsilicate, methylcellulose, pectin, casein, gelatin, polyethylene oxide,polyvinyl alcohol, povidone, propylene glycol, alginate, silicondioxide, silicon dioxide colloidal, sodium alginate and other alginates,and tragacanth. Of the foregoing suspending agents, xanthan gum is themost preferred. As those skilled in the art would recognize, wide rangesof suspending agent can be employed in the contrast medium of theinvention, as needed or desired. Preferably, however, the suspendingagent is present in an amount of at least about 0.05% by weight, morepreferably at least about 0.1% by weight, and generally less than about1% by weight, even more preferably less than about 0.5% by weight.

As mentioned above, in a preferable embodiment, the contrast medium ishypoosmotic. By "hypoosmotic"(or "hypoosmolarity"), as used herein, itis meant a contrast medium which has less osmolarity, measured inmilliosmoles per liter of solution, than the bodily fluids of thepatient. Osmolarity is a term that is well known in the art, and isdiscussed for example, in Guyton, Arthur C., Textbook of MedicalPhysiology, Chapters 4 and 33, 6th ed., W. B. Saunders Company,Philadelphia, Pa. (1981), the disclosures of which are herebyincorporated herein by reference, in their entirety. The osmolarity ofnormal biological fluids of a patient, which would surround the contrastmedium in use (for example, the fluids in and behind the membranoustissues forming or adjacent to the gastrointestinal tract walls, wheregastrointestinal use of the contrast medium is contemplated), have anosmolarity between 280 and 305 milliosmoles/liter. The osmolarity of thehypoosmotic contrast medium of the present invention is typically lessthan 280 milliosmoles/liter, preferably between about 200 and about 270milliosmoles/liter, more preferably between about 220 and about 260milliosmoles/liter, and most preferably between about 250 to about 260milliosmoles/liter.

The hypoosmotic nature of this preferred embodiment of the inventionserves to prevent or greatly minimize the flow of water into the regionwhere the contrast medium is being employed. Such an influx of water hasbeen found to be deleterious to the most effective use of the contrastmedium. Specifically, it has been found that such an influx of water mayserve to increase the motility of the contrast medium through the areato be imaged thereby lessening the time period available to theradiologist to carry out an effective scan. It may also cause undesireddistension (overdistention) in the area in which the contrast agent isadministered resulting in a distorted image, and may produce patientdiscomfort such as, for example, diarrhea and gastrointestinal upset, inthe case of gastrointestinal use. Such an influx of water may also serveto dilute the contrast medium, necessitating the administration of ahigher dose of active ingredient to achieve the desired contrastenhancement effect, thereby increasing possible toxicity. With ahypoosmotic contrast medium, as described herein, many of theseundesired effects may be eliminated or minimized, providing a preferredand highly effective contrast medium for magnetic resonance imaging.

As those skilled in the art will recognize, the osmolarity of a solutionmay be controlled by regulating the use of osmotically active materialsin the contrast medium formulation. Osmotically active materials includesuch physiologically compatible compounds as monosaccharide sugars orsugar alcohols, disaccharide sugars, amino acids, and various syntheticcompounds. Suitable monosaccharide sugars or sugar alcohols include, forexample, erythrose, threose, ribose, arabinose, xylose, lyxose, allose,altrose, glucose, mannose, idose, galactose, talose, ribulose, fructose,sorbitol, mannitol, and sedoheptulose, with preferable monosaccharidesbeing fructose, mannose, xylose, arabinose, mannitol and sorbitol.Suitable disaccharide sugars include, for example, lactose, sucrose,maltose, and cellobiose. Suitable amino acids include, for example,glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine,aspartic acid, glutamic acid, lysine, arginine and histidine. Syntheticcompounds include, for example, propylene glycol, polypropylene glycol,ethylene glycol, polyethylene glycol and polyvinylpyrrolidone. Variousother suitable osmotically active materials are well known to thoseskilled in the art, and are intended to be within the scope of the termosmotically active agent as used herein. Typically, to achieve thepreferred ranges of osmolarity in the contrast medium of the invention,less than about 25 g/l, more preferably less than about 20 g/l, evenmore preferably less than about 15 g/l, and still more preferably lessthan about 10 g/l of the osmotically active materials are employed, andin some instances no osmotically active materials are employed. A mostpreferred range of osmotically active materials is generally betweenabout 1 and about 10 g/l.

Although the most desirable pH of the contrast medium of the presentinvention may vary, as those skilled in the art will recognize, thepreferred pH range for most diagnostic uses is generally between about 3and about 10 pH units, more preferably between about 5 and 8 pH units.The desired pH can be achieved and maintained through the use ofphysiologically compatible pH regulating additives such as suitablebases, buffers, and the like, as one skilled in the art will recognize.Particularly preferred bases include sodium bicarbonate and sodiumhydroxide, especially sodium bicarbonate. Particularly preferred buffersinclude sodium acetate and glacial acetic acid buffer.

The present invention is useful in imaging a patient generally, and/orin specifically diagnosing the presence of diseased tissue in a patient.The imaging process of the present invention may be carried out byadministering a contrast medium of the invention to a patient, and thenscanning the patient using magnetic resonance imaging to obtain visibleimages of an internal region of a patient and/or of any diseased tissuein that region. By region of a patient, it is meant the whole patient ora particular area or portion of the patient. The contrast medium isparticularly useful in providing images of the gastrointestinal region,but can also be employed more broadly such as in imaging the vasculatureor in other ways as will be readily apparent to those skilled in theart. The phrase gastrointestinal region or gastrointestinal tract, asused herein, includes the region of a patient defined by the esophagus,stomach, small and large intestines and rectum. The phrase vasculature,as used herein, denotes the blood vessels in the body or in an organ orpart of the body. The patient can be any type of animal or mammal, butmost preferably is a human.

As one skilled in the art would recognize, administration may be carriedout in various fashions, such as intravascularly, orally, rectally,etc., using a variety of dosage forms. When the region to be scanned isthe gastrointestinal region, administration of the contrast medium ofthe invention is preferably carried out orally or rectally. The usefuldosage to be administered and the particular mode of administration willvary depending upon the age, weight and the particular mammal and regionthereof to be scanned, and the particular medium of the invention to beemployed. Typically, dosage is initiated at lower levels and increaseduntil the desired contrast enhancement is achieved. Various combinationsof biocompatible polymers may be used to modify the relaxation behaviorof the medium or to alter properties such as the viscosity, osmolarityor palatability (in the case of orally administered materials). Incarrying out the method of the present invention, the contrast mediumcan be used alone, or in combination with other diagnostic, therapeuticor other agents. Such other agents include excipients such asphysiologically compatible flavoring or coloring materials. Particularlypreferred flavoring agents include sucrose and/or natural citrus flavor.In addition, if desired, the contrast media of the invention may beencapsulated in liposomes or in other suitable delivery vehicles. Thepolymer or polymer and contrast agent and/or gas admixture may besterilized by autoclaving prior to use, if desired.

The magnetic resonance imaging techniques which are employed areconventional and are described, for example, in D. M. Kean and M. A.Smith, Magnetic Resonance Imaging: Principles and Applications, (Williamand Wilkins, Baltimore 1986). Contemplated MRI techniques include, butare not limited to, nuclear magnetic resonance (NMR) and electronic spinresonance (ESR). The preferred imaging modality is NMR.

As will be apparent to those skilled in the art, the polymer or polymeradmixture with contrast agent and/or gas, when employed in magneticresonance imaging, may operate as a T1, T2 or proton density contrastmedium, depending upon the type of polymer used, the molecular weight ofthe polymer, the concentration of the polymer, the type of contrastagent mixed with the polymer, the type of MRI modality chosen, and thedetails of the pulse sequence employed for MRI imaging, and all suchmechanisms of operation are considered to be within the ambit of thepresent invention.

The media of the present invention have been shown to be extremelyuseful as contrast enhancement media in magnetic resonance imaging,particularly in imaging of the gastrointestinal region. By employing thepolymers alone or by combining a contrast agent with the polymers inaccordance with the present invention, lower overall concentrations ofthe contrast agents may be used to achieve the same, or in many cases abetter degree of, contrast enhancement results. This has benefits notonly in terms of toxicity, by avoiding the use of large amounts of thepotentially toxic contrast agents, but also in terms of cost, since lessof the often more expensive conventional contrast agents are used.Furthermore, in the case of negative contrast agents based onsuperparamagnetic particles, magnetic susceptibility artifacts will bereduced through the ability to use a lower dose of the contrast agent.These and other advantages described herein of the present inventionwill be readily apparent to those skilled in the art, upon reading thepresent disclosure.

A particularly preferred formulation of the contrast medium of theinvention which is useful in magnetic resonance imaging is an aqueoussolution of the following components:

(i) 5-10 g/l polygalacturonic acid having a weight average molecularweight of less than 30,000;

(ii) 20-70 mg/l Mn(II);

(iii) 0.5-3.0 g/l xanthan gum;

(iv) 2-6 g/l sodium bicarbonate;

(v) 2-6 g/l glacial acetic acid or sodium acetate buffer;

(vi) 2-6 g/l glycine; and, optionally,

(vii) a flavorant selected from the group consisting of sucrose andnatural citrus flavor. The pH of the above referenced formulation ispreferably between about 5 and 8 pH units, and the formulationpreferably has an osmolarity of between about 250 to about 260milliosmoles/liter.

The present invention is further described in the following Examples.These Examples are not to be construed with as limiting the scope of theappended claims.

EXAMPLES Example 1

The polymer polyethylene glycol (PEG), having a molecular weight about8000, was dissolved in water to various concentrations (w/w; by weight).To some of the aqueous PEG solutions was then added the contrast agentGd-DTPA, such that the final concentration of Gd-DTPA was 1 mM. Therelaxivity or relaxation rate (1/T1 and 1/T2) of the PEG and the PEG andGd-DTPA solutions was then tested in vitro using a Toshiba MR-50A 0.5Tesla (T) whole body scanner. The results are shown in Table 1 and FIG.2. As the results indicate, in the presence of PEG the relaxivity ofboth water and Gd-DTPA is increased.

At best, it would be expected that the relaxation rates would be simplyadditive, i.e. the relaxation rate observed would be the sum of therelaxation rates of the individual components. However, an inspection ofTable 1 and FIG. 2 shows that the 1/T1 relaxation rate of 40% (w/w) PEG8000 in water was 1.35±0.04 at 0.5 T and the 1/T1 relaxation rate for 1mM Gd-DTPA in water was measured to be 4.68±0.09 at 0.5 T. If the rateswere simply additive it would be expected that the observed relaxationrate for 1 mM Gd-DTPA in a 40% (w/w) PEG 8000 solution would beapproximately 4.68+1.35=6.03, at 0.5 T. The results in Table 1 and FIG.2, however, surprisingly reveal that the relaxation rate for thePEG/water/Gd-DTPA mixture was in fact 12.81±0.72 at 0.5 T. In sum, forboth T1 and T2 relaxation rates, it has been observed that therelaxation rate of the polymer/Gd-DTPA admixture is greater than the sumof the relaxation rates of the PEG solution and the Gd-DTPA solutionalone.

The foregoing result is in hindsight believed to arise as a consequenceof the exclusion of the Gd-DTPA from the immediate environment of thePEG molecules so that the effective concentration of the Gd-DTPA isincreased in the water not bound to the polymer. However, the presentinvention is not intended to be limited by any theory of operation.

                  TABLE 1                                                         ______________________________________                                        Relaxivities at 0.5T for PEG 8000/Water Mixtures                              In the Absence and Presence of 1 mM Gd-DTPA                                   Sample             1/T1 (1/sec)                                                                             1/T2 (1/sec)                                    ______________________________________                                        water              0.21 ± 0.04                                                                           0.65 ± 0.04                                  10% PEG/water      0.41 ± 0.03                                                                           0.85 ± 0.03                                  20% PEG/water      0.64 ± 0.02                                                                           1.12 ± 0.06                                  30% PEG/water      0.96 ± 0.02                                                                           1.57 ± 0.05                                  40% PEG/water      1.35 ± 0.04                                                                           2.25 ± 0.08                                  1 mM Gd-DTPA/water 4.68 ± 0.18                                                                           5.65 ± 0.03                                  10% PEG/water/1 mM Gd-DTPA                                                                       5.58 ± 0.23                                                                           6.86 ± 0.02                                  20% PEG/water/1 mM Gd-DTPA                                                                       7.19 ± 0.53                                                                           8.69 ± 0.07                                  30% PEG/water/1 mM Gd-DTPA                                                                       9.42 ± 0.58                                                                           12.11 ± 0.08                                 40% PEG/water/1 mM Gd-DTPA                                                                       12.81 ± 0.72                                                                          17.62 ± 0.15                                 ______________________________________                                    

Example 2

Example 1 was substantially repeated, except that the polymer dextrosewas employed instead of PEG. The results are shown in FIG. 3. As theresults indicate, in the presence of dextrose the relaxivity of bothwater and Gd-DTPA is increased.

As FIG. 3 illustrates, again, as with PEG, the relaxivity of thedextrose and Gd-DTPA solution is larger than the sum of the individualrelaxation rates.

Example 3

Example 1 was substantially repeated except that an aqueous solution of1 mM Gd-DTPA, 30% (w/w) PEG 8000 and 10% (w/w) dextrose was prepared andT1 was reported. A 1/T1 relaxivity or relaxation rate of 11.67±1.09(1/sec) at 0.5 T was observed.

Examples 1, 2 and 3 show that different polymers may be used topreferentially alter the T1 or T2 relaxation rates of a solution. Forexample, as shown in Example 3, a solution of 1 mM Gd-DTPA and 30% PEG8000 and 10% dextrose exhibits a T1 relaxation rate of 11.67±1.09(1/sec) at 0.5 T. By comparison, 1 mM Gd-DTPA and 30% PEG 8000 insolution exhibits a T1 relaxation rate of 9.42±0.58 (1/sec) at 0.5 T,and 1 mM Gd-DTPA and 10% dextrose in solution exhibits a T1 relaxationrate of 2.33±0.02 (1/sec) at 0.5 T.

Example 4

Example 1 was substantially repeated, except that 10% (w/w) cellulose, alow toxicity polymer that is not degraded within the gastrointestinaltract, was employed, in aqueous solution with and without differentconcentrations of a ferrite contrast agent and with and without carbondioxide gas.

The results are shown in Table 2 and FIG. 4. As the results indicate,cellulose is also an efficient T2 relaxation agent, and the T2relaxivity of cellulose may be improved by mixing with a gas such ascarbon dioxide. In addition, the results show that cellulose may becombined with a superparamagnetic contrast agent such as ferrites suchthat the combined polymer/ferrite contrast agent, whether mixed with gasor not, is superior in terms of relaxivity, as compared with either thepolymer or ferrite alone. Specifically, from the results, it can be seenthat the T2 relaxivity for a sample containing 10% cellulose with 10 mMferrites after treating with gas has a higher T2 relaxivity than a 40 mMdispersion of ferrites in water. The immediate conclusion is that itwould be possible to reduce the dose of ferrites administered by atleast a factor of 4 and still obtain the same degree of contrastenhancement. This would have clear benefits in terms of decreasing thepotential toxicity of the contrast agent.

                  TABLE 2                                                         ______________________________________                                        Relaxivities at 0.5T for Water/Ferrite                                        and Cellulose/Water/Ferrite mixtures                                          Sample           1/T1 (1/sec)                                                                             1/T2 (1/sec)                                      ______________________________________                                        water            0.27 ± 0.05                                                                            0.55 ± 0.06                                   + 10 mM ferrites 1.16 ± 0.01                                                                            5.45 ± 0.07                                   + 20 mM ferrites 1.92 ± 0.03                                                                           10.20 ± 0.10                                   + 40 mM ferrites 3.60 ± 0.10                                                                           20.24 ± 0.43                                   10% cellulose in water +                                                                       --         12.76 ± 0.08                                   pressurized with gas                                                                           0.76 ± 0.01                                                                           15.95 ± 0.05                                   gas + 10 mM ferrites                                                                           1.98 ± 0.03                                                                           22.82 ± 0.62                                   gas + 20 mM ferrites                                                                           2.41 ± 0.03                                                                           26.75 ± 0.32                                   gas + 40 mM ferrites                                                                           4.15 ± 0.11                                                                           37.42 ± 0.94                                   ______________________________________                                    

Example 5

A 2 % aqueous solution of the polymer polygalacturonic acid in admixtureMn(II) was prepared. The relaxivity (1/T1 and 1/T2) of the solution wasthen tested in vitro using a Toshiba MRT-50A 0.5 Tesla (T) whole bodyscanner. The 1/T1 was measured at 41.0±1.92 mmol⁻¹ sec⁻¹, and the 1/T2was measured at 79.41±3.20 mmol⁻¹ sec⁻¹.

Example 6

A 0.5 % aqueous solution of the polymer polygalacturonic acid wasprepared. To the solution was then added 0.1 mM Mn(II). The relaxivity(1/T1 and 1/T2) of the solution was tested in vitro using a ToshibaMRT-50A 0.5 Tesla (T) whole body scanner. The 1/T1 was measured at1.20±0.056 sec⁻¹, and the 1/T2 was measured at 4.78±0.001 sec⁻¹.

Example 7

The procedures of Example 6 were substantially followed, except thatsodium hydroxide was added to the solution in an amount sufficient toraise the pH from 2 (as in Example 6), to a pH of 4, 6, 7, and 8,respectively. The relaxivity (1/T1 and 1/T2) of the solutions at thesevarious pH levels was tested in vitro using a Toshiba MRT-50A 0.5 Tesla(T) whole body scanner. The results are shown below in Table 3.

                  TABLE 3                                                         ______________________________________                                        Relaxivities at 0.5T For                                                      Water/Polygalacturonic Acid/Mn (II) Mixtures                                  At Varying pH Levels                                                          Sample pH     1/T1 (1/sec)                                                                             1/T2 (1/sec)                                         ______________________________________                                        pH 4          4.15 ± 0.21                                                                           6.78 ± 0.14                                       pH 6          4.10 ± 0.19                                                                           7.94 ± 0.32                                       pH 7          3.73 ± 0.22                                                                           6.29 ± 0.24                                       pH 8          4.11 ± 0.55                                                                           6.64 ± 0.27                                       ______________________________________                                    

Example 8

Aqueous samples of several different compounds chelated to or inadmixture with Mn(II) were prepared. In the aqueous samples, theconcentration of galacturonate monomer was 0.5%, the concentration ofalgin was 0.5%, and the concentration of cellulose was 0.25%. Therelaxivity or relaxation rate of each was then tested in vitro using aToshiba MRT-50A 0.5 Tesla (T) whole body scanner. The results are shownas R1 and R2 values, which represents relativities per concentration ofMn(II), that is, relaxivity per mmol⁻¹ liter sec⁻¹ (1/T1 mmol⁻¹ litersec^(-1;) 1/T2 mmol⁻¹ liter sec⁻¹). R1 and R2 thus define the effect ofthe compounds on relaxivity for a standard concentration of Mn(II). Theresults are shown below in Table 4.

As revealed by Table 4, Mn(II), as manganese chloride, has an 1/T1 and1/T2 relaxivity of about 8 and 39 respectively. The chelate of Mn(II),manganese N,N"-bis-carboxyamido-methyl-N-(2-methoxyethylene)-ethylenediamine-N,N'-diacetate(Mn(II)-EDTA-MEA), has a significantly lower relaxivity, with an 1/T1and 1/T2 of about 3 and 8 respectively. The monomer of galacturonate hasvirtually no effect on the relaxivity of Mn(II). On the other hand, theMn(II)/algin and Mn(II)/cellulose contrast media of the invention, werefound to provide significant and unexpected improvement in relaxivityover Mn(II), Mn(II)-EDTA-MEA and Mn(II) galacturonate monomer, as shownin Table 4.

                  TABLE 4                                                         ______________________________________                                        Relaxivities at 0.5T For Various                                              Mn(II)-Containing Aqueous Samples                                             Sample          R1         R2                                                 ______________________________________                                        MnCl.sub.2      8.73 ± 0.28                                                                           39.45 ± 0.52                                    Mn-EDTA-MEA     3.04 ± 0.15                                                                            7.98 ± 0.23                                    Chelate                                                                       MnCl.sub.2 and  9.01 ± 0.41                                                                           37.36 ± 0.10                                    Galacturonate                                                                 Monomer Admixture                                                             MnCl.sub.2 and  20.3 ± 1.95                                                                           40.20 ± 0.38                                    Algin Admixture                                                               MnCl.sub.2 and  21.00 ± 0.63                                                                           31.0 ± 1.20                                    Cellulose                                                                     Admixture                                                                     ______________________________________                                    

Example 9

Aqueous samples of polygalacturonic acid of varying molecular weightsand pectin, in admixture with manganese, were prepared. High molecularweight polygalacturonic acid having a weight average molecular weight ofabout 40,000, was obtained from Fluka Chemical Co., Ronkonkoma, N.Y. Lowmethoxy pectin, D075-X Apple Pectin, was obtained from Spreda Corp.,Prospect Ky. Decagalacturonic acid (10 galacturonic acid monomer units)having a weight average molecular weight of about 1,900, was prepared bysubstantially following the procedures of Lakatos et al., U.S. Pat. No.4,225,592. Low molecular weight polygalacturonic acid, having a weightaverage molecular weight of about 2,200, was prepared by hydrolyzing thelow methoxy pectin (D075-X Apple Pectin, obtained from Spreda Corp.,Prospect Ky.) substantially following the procedures of Mihashi,Pharmaceutical J., Vol. 81, pp. 1000-1002 (1961). Decagalacturonic acid(40%) and high molecular weight polygalacturonic acid (60%) were alsomixed together to form a polygalacturonic acid composition having aweight average molecular weight of about 25,000. All polymercompositions were formulated to 0.6% polymer concentration.

Each polymer was then mixed with a 1 mM concentration of Mn(II). Sampleswere serially diluted with deionized water to give concentrations from0.0125 to 0.5 mM Mn(II) and relaxivity (1/T1 and 1/T2) was tested invitro using a Toshiba MRT-50A 0.5 Tesla (T) whole body scanner.Relaxivity results were regressed against concentration to determine R1and R2 (1/T1 mmol⁻¹ liter sec^(-1;) 1/T2 mmol⁻¹ liter sec⁻¹. The resultsare shown below in Table 5.

As revealed by Table 5, better relaxivity is achieved with manganese inadmixture with low molecular weight polygalacturonic acid polymers(below 30,000 weight average molecular weight), than with higher weightpolygalacturonic acid polymers. Also, as the data shows,polygalacturonic acid provides better relaxivity than pectin, whenadmixed with manganese.

                  TABLE 5                                                         ______________________________________                                        Relaxivities at 0.5T For Aqueous Samples of                                   Pectin and Polygalacturonic Acids With Mn(II)                                 Sample          R1         R2                                                 ______________________________________                                        Decagalacturonic                                                                              35.33 ± 0.62                                                                          61.02 ± 0.89                                    Acid and Mn(II)                                                               Low MW          46.11 ± 0.35                                                                          67.98 ± 1.26                                    Polygalacturonic                                                              Acid and Mn(II)                                                               40%             42.62 ± 0.29                                                                          67.28 ± 0.46                                    Decagalacturonic                                                              Acid and                                                                      60% High MW                                                                   Polygalacturonic                                                              Acid and Mn(II)                                                               Low Methoxy     16.53 ± 0.88                                                                          36.53 ± 0.69                                    Pectin and Mn(II)                                                             High MW         28.99 ± 0.04                                                                          55.32 ± 1.11                                    Polygalacturonic                                                              Acid and Mn(II)                                                               ______________________________________                                    

Example 10

Two formulations of contrast media were prepared using differentmolecular weights of polygalacturonic acid. For one formulation, highmolecular weight polygalacturonic acid having a weight average molecularweight of about 40,000, obtained from Fluka Chemical Co., Ronkonkoma,N.Y., was used. For the second formulation, low molecular weightpolyglacturonic acid having a weight average molecular weight of about2,200, was prepared by hydrolyzing the low methoxy pectin (D075-X ApplePectin, obtained from Spreda Corp., Prospect Ky.) substantiallyfollowing the procedures of Mihashi, Pharmaceutical J., Vol. 81, pp.1000-1002 (1961). Specifically, to prepare the low molecular weightpolygalacturonic acid, ten grams of the DO75-X Apple Pectin washydrolyzed in 100 ml of a 5% HCl solution for 5 hours at a constanttemperature of 85° C. The solution was then vacuum filtered resulting ina dark brown precipitate and a yellow-colored solution. A decolorizationstep was then carried out as follows. First, two grams of activatedcharcoal were added to the solution and the solution heated to 80° C.for 30 minutes. The mixture was filtered, resulting in a clear colorlesssolution. The colorless solution was then evaporated to drynessresulting in the desired low molecular weight polygalacturonic acid as ayellow-brown powder.

The high and low molecular weight polygalacturonic acid polymers wereeach formulated as an aqueous solution as shown in Table 6 below, toform hypoosmotic solutions having an osmolarity of between 220 and 260milliosmoles/liter.

                  TABLE 6                                                         ______________________________________                                        Aqueous Formulations of Mn(II)                                                With High and Low Molecular Weight                                            Polygalacturonic Acids                                                        Ingredient              Amount                                                ______________________________________                                        Polygalacturonic Acid   6      g/l                                            (high or low MW,                                                              as described above)                                                           Mn.sup.+2 (as MnCl.sub.2) (ACS)                                                                       50     mg/l                                           (obtained from Spreda Corp.,                                                  Prospect, KY)                                                                 Xanthan Gum (0.100%)    1      g/l                                            (Keltrol RD NF, obtained                                                      from Kelco, Division of                                                       Merck, San Diego, CA)                                                         Sodium Bicarbonate (1 M;                                                                              ≈50 ml (to                                    USP/NF) (obtained from  raise pH                                              Spectrum Pharmaceuticals,                                                                             to 6.0)                                               Gardena, CA)                                                                  Glacial acetic acid (300 mM;                                                                          30     ml                                             USP/NF) (obtained from Spectrum                                               Pharmaceuticals, Gardena, CA                                                  Propylene Glycol        2      g/l                                            (obtained from Spectrum                                                       Pharmaceuticals, Gardena, CA)                                                 Natural Citrus Flavoring                                                                              2      g/l                                            (obtained from Firmenich, SA,                                                 Geneva, Switzerland)                                                          ______________________________________                                    

Relaxivity (1/T1 and 1/T2) for each formulation was tested in vitrousing a Toshiba MRT-50A 0.5 Tesla (T) whole body scanner. Relaxivityresults were regressed against concentrations of Mn(II) to determine R1and R2 (1/T1 mmol⁻¹ liter sec^(-1;) 1/T2 mmol⁻¹ liter sec⁻¹) for eachformulation. The results are shown below in Table 7.

As revealed by Table 7, although the relaxivity of both formulations isexcellent, the low molecular weight polygalacturonic acid formulationprovided even better relaxivity than its high molecular weightcounterpart.

                  TABLE 7                                                         ______________________________________                                        Relaxivities at 0.5T For Aqueous Formulations                                 of Mn(II) With High and Low Molecular Weight                                  Polygalacturonic Acids                                                        Formulation    R1         R2                                                  ______________________________________                                        High MW        28.99 ± 0.56                                                                          55.32 ± 1.11                                     Polygalacturonic                                                              Acid Formulation                                                              Low MW          37.4 ± 1.45                                                                           69.5 ± 1.37                                     Polygalacturonic                                                              Acid Formulation                                                              ______________________________________                                    

Various modifications of the invention in addition to those shown anddescribed herein will be apparent to those skilled in the art from theforegoing description. Such modifications are also intended to fallwithin the scope of the appended claims.

What is claimed is:
 1. A contrast medium for use in magnetic resonanceimaging of a patient comprising an aqueous solution or suspension of abiocompatible polymer in admixture with a contrast agent bound to acomplexing agent, wherein the contrast medium is hypoosmotic to bodilyfluids of the patient.
 2. A contrast medium of claim 1 wherein thehypoosmotic contrast medium has an osmolarity of less than 280milliosmoles/liter.
 3. A contrast medium of claim 2 wherein theosmolarity is between about 200 and about 270 milliosmoles/liter.
 4. Acontrast medium of claim 3 wherein the osmolarity is between about 220and about 260 milliosmoles/liter.
 5. A contrast medium of claim 4wherein the osmolarity is between about 250 and about 260milliosmoles/liter.
 6. A contrast medium of claim 1 wherein the polymeris a natural polymer.
 7. A contrast medium of claim 1 wherein thepolymer is a synthetic polymer.
 8. A contrast medium of claim 1 whereinthe polymer is a polysaccharide.
 9. A contrast medium of claim 1 whereinthe polymer is a polyuronic acid.
 10. A contrast medium of claim 1wherein the polymer has a weight average molecular weight of less than30,000.
 11. A contrast medium of claim 1 wherein the polymer is apolysaccharide selected from the group consisting of arabinans,fructans, fucans, galactans, galacturonans, glucans, mannans, xylans,levan, fucoidan, carrageenan, galactocarolose, pectin, pectic acid,amylose, pullulan, glycogen, amylopectin, cellulose,carboxylmethylcellulose, hydroxypropylmethylcellulose, dextran,pustulan, chitin, agarose, keratan, chondroitin, dermatan, hyaluronicacid, alginic acid, and polysaccharides containing at least one aldose,ketose, acid or amine selected from the group consisting of erythrose,threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose,mannose, gulose, idose, galactose, talose, erythrulose, ribulose,xylulose, psicose, fructose, sorbose, tagatose, glucuronic acid,gluconic acid, glucaric acid, galacturonic acid, mannuronic acid,glucosamine, galactosamine and neuraminic acid.
 12. A contrast medium ofclaim 1 wherein the polymer is selected from the group consisting ofpolyethylenes, polyoxyethylenes, polypropylenes, pluronic acids,pluronic alcohols, polyvinyls, and polyvinylpyrrolidones.
 13. A contrastmedium of claim 1 wherein the polymer is polygalacturonic acid.
 14. Acontrast medium of claim 1 wherein the polymer is polyethylene glycol.15. A contrast medium of claim 1 wherein the contrast agent is selectedfrom the group consisting of paramagnetic, superparamagnetic and protondensity contrast agents.
 16. A contrast medium of claim 15 wherein thecontrast agent is a paramagnetic contrast agent which is a transition,lanthanide or actinide element.
 17. A contrast medium of claim 16wherein the paramagnetic contrast agent is selected from the groupconsisting of Gd(III), Mn(II), Cu(II), Cr(III), Fe(II), Fe(III), Co(II),Er(II), Ni(II), Eu(III) and Dy(III).
 18. A contrast medium of claim 17wherein the paramagnetic contrast agent is Mn(II).
 19. A contrast mediumof claim 1 further comprising a suspending agent.
 20. A contrast mediumof claim 19 wherein the suspending agent is selected from the groupconsisting of xanthum gum, acacia, agar, alginic acid, aluminummonostearate, bassorin, karaya, gum arabic, unpurified bentonite,purified bentonite, bentonite magma, calcium carboxymethylcellulose,sodium carboxymethylcellulose, carrageenan, microcrystalline cellulose,dextran, gelatin, guar gum, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium aluminumsilicate, methylcellulose, pectin, casein, gelatin, polyethylene oxide,polyvinyl alcohol, povidone, propylene glycol, alginate, silicondioxide, silicon dioxide colloidal, alginate, sodium alginate, andtragacanth.
 21. A contrast medium of claim 20 wherein the suspendingagent is xanthan gum.
 22. A contrast medium of claim 1 furthercomprising an osmotically active material.
 23. A contrast medium ofclaim 22 wherein the osmotically active material is selected from thegroup consisting of erythrose, threose, ribose, arabinose, xylose,lyxose, allose, altrose, glucose, mannose, idose, galactose, talose,ribulose, fructose, sorbitol, mannitol, sedoheptulose, lactose, sucrose,maltose, cellobiose, glycine, serine, threonine, cysteine, tyrosine,asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine,histidine, propylene glycol, polypropylene glycol, ethylene glycol,polyethylene glycol and polyvinylpyrrolidone.
 24. A contrast medium ofclaim 23 wherein the osmotically active material is glycine.
 25. Acontrast medium of claim 1 further comprising a pH regulating additiveeffective to maintain a pH of between about 3 and about
 10. 26. Acontrast medium of claim 25 wherein the pH regulating additive iseffective to maintain a pH of between about 3 and
 8. 27. A contrastmedium of claim 1 further comprising a biocompatible gas.
 28. A contrastmedium of claim 27 wherein the biocompatible gas is selected from thegroup consisting of air, oxygen, carbon dioxide, nitrogen, xenon, neonand argon.
 29. A contrast medium of claim 1 further comprising asuspending agent, an osmotically active material, and a pH regulatingadditive effective to maintain a pH of between about 3 and about
 10. 30.A contrast medium of claim 29 wherein the polymer is polygalacturonicacid having a weight average molecular weight of less than 30,000, thecontrast agent is Mn(II), the suspending agent is xanthan gum, theosmotically active material is glycine, and the pH regulating additiveis selected from the group consisting of sodium bicarbonate, glacialacetic acid and sodium acetate buffer, and wherein the contrast mediumhas an osmolarity of between about 200 and about 270 milliosmoles/liter.31. A contrast medium of claim 29 wherein the polymer ispolygalacturonic acid having a weight average molecular weight of lessthan 30,000 in an amount between about 5 and about 10 grams/liter, thecontrast agent is Mn(II) in an amount between about 20 and about 70milligrams/liter, the suspending agent is xanthan gum in an amountbetween about 0.5 and about 3.0 grams/liter, the osmotically activematerial is glycine in an amount between about 2 and about 6grams/liter, and the pH regulating additive is effective to maintain thepH between about 5 and about 8 and is a combination of sodiumbicarbonate in an amount between about 2 and about 6 grams/liter andsodium acetate buffer in an amount between about 2 and about 6grams/liter, and wherein the contrast medium has an osmolarity ofbetween about 250 and about 260 milliosmoles/liter.
 32. A contrastmedium of claim 1 which is a contrast medium for use in imaging agastrointestinal region of a patient.
 33. A contrast medium of claim 1which is a contrast medium for use in imaging vasculature of a patient.34. A method of providing an image of an internal region of a patientcomprising (i) administering to the patient a diagnostically effectiveamount of a contrast medium comprising an aqueous solution or suspensionof a biocompatible polymer in admixture with a contrast agent bound to acomplexing agent, wherein the contrast medium is hypoosmotic to bodilyfluids of the patient, and (ii) scanning the patient using magneticresonance imaging to obtain visible images of the region.
 35. A methodof claim 34 wherein the region is the gastrointestinal region.
 36. Amethod of claim 34 wherein the region is the vasculature.
 37. A methodof claim 34 wherein the hypoosmotic contrast medium has an osmolarity ofless than 280 milliosmoles/liter.
 38. A method of claim 37 wherein theosmolarity is between about 200 and about 270 milliosmoles/liter.
 39. Amethod of claim 38 wherein the osmolarity is between about 220 and about260 milliosmoles/liter.
 40. A method of claim 39 wherein the osmolarityis between about 250 and about 260 milliosmoles/liter.
 41. A method ofclaim 34 wherein the polymer is a natural polymer.
 42. A method of claim34 wherein the polymer is a synthetic polymer.
 43. A method of claim 34wherein the polymer is a polysaccharide.
 44. A method of claim 34wherein the polymer is a polyuronic acid.
 45. A method of claim 34wherein the polymer has a weight average molecular weight of less than30,000.
 46. A method of claim 34 wherein the polymer is a polysaccharideselected from the group consisting of arabinans, fructans, fucans,galactans, galacturonans, glucans, mannans, xylans, levan, fucoidan,carrageenan, galactocarolose, pectin, pectic acid, amylose, pullulan,glycogen, amylopectin, cellulose, carboxylmethylcellulose,hydroxypropylmethylcellulose, dextran, pustulan, chitin, agarose,keratan, chondroitin, dermatan, hyaluronic acid, alginic acid, andpolysaccharides containing at least one aldose, ketose, acid or amineselected from the group consisting of erythrose, threose, ribose,arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose,idose, galactose, talose, erythrulose, ribulose, xylulose, psicose,fructose, sorbose, tagatose, glucuronic acid, gluconic acid, glucaricacid, galacturonic acid, mannuronic acid, glucosamine, galactosamine andneuraminic acid.
 47. A method of claim 34 wherein the polymer isselected from the group consisting of polyethylenes, polyoxyethylenes,polypropylenes, pluronic acids, pluronic alcohols, polyvinyls, andpolyvinylpyrrolidones.
 48. A method of claim 34 wherein the polymer ispolygalacturonic acid.
 49. A method of claim 34 wherein the polymer ispolyethylene glycol.
 50. A method of claim 34 wherein the contrast agentis selected from the group consisting of paramagnetic, superparamagneticand proton density contrast agents.
 51. A method of claim 50 wherein thecontrast agent is a paramagnetic contrast agent which is a transition,lanthanide or actinide element.
 52. A method of claim 51 wherein theparamagnetic contrast agent is selected from the group consisting ofGd(III), Mn(II), Cu(II), Cr(III), Fe(II), Fe(III), Co(II), Er(II),Ni(II), Eu(III) and Dy(III).
 53. A method of claim 52 wherein theparamagnetic contrast agent is Mn(II).
 54. A method of claim 34 furthercomprising a suspending agent.
 55. A method of claim 54 wherein thesuspending agent is selected from the group consisting of xanthum gum,acacia, agar, alginic acid, aluminum monostearate, bassorin, karaya, gumarabic, unpurified bentonite, purified bentonite, bentonite magna,calcium carboxymethylcellulose, sodium carboxymethylcellulose,carrageenan, microcrystalline cellulose, dextran, gelatin, guar gum,hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, magnesium aluminum silicate,methylcellulose, pectin, casein, gelatin, polyethylene oxide, polyvinylalcohol, povidone, propylene glycol, alginate, silicon dioxide, silicondioxide colloidal, alginate, sodium alginate, and tragacanth.
 56. Amethod of claim 55 wherein the suspending agent is xanthan gum.
 57. Amethod of claim 34 further comprising an osmotically active material.58. A method of claim 57 wherein the osmotically active material isselected from the group consisting of erythrose, threose, ribose,arabinose, xylose, lyxose, allose, altrose, glucose, mannose, idose,galactose, talose, ribulose, fructose, sorbitol, mannitol,sedoheptulose, lactose, sucrose, maltose, cellubiose, glycine, serine,threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid,glutamic acid, lysine, arginine, histidine, propylene glycol,polypropylene glycol, ethylene glycol, polyethylene glycol andpolyvinylpyrrolidone.
 59. A method of claim 58 wherein the osmoticallyactive material is glycine.
 60. A method of claim 34 further comprisinga pH regulating additive effective to maintain a pH of between about 3and about
 10. 61. A method of claim 60 wherein the pH regulatingadditive is effective to maintain a pH of between about 3 and
 8. 62. Amethod of claim 34 further comprising a biocompatible gas.
 63. A methodof claim 62 wherein the biocompatible gas is selected from the groupconsisting of air, oxygen, carbon dioxide, nitrogen, xenon, neon andargon.
 64. A method of claim 34 further comprising a suspending agent,an osmotically active material, and a pH regulating additive effectiveto maintain a pH of between about 3 and about
 10. 65. A method of claim64 wherein the polymer is polygalacturonic acid having a weight averagemolecular weight of less than 30,000, the contrast agent is Mn(II), thesuspending agent is xanthan gum, the osmotically active material isglycine, and the pH regulating additive is selected from the groupconsisting of sodium bicarbonate, glacial acetic acid and sodium acetatebuffer, and wherein the contrast medium has an osmolarity of betweenabout 200 and about 270 milliosmoles/ liter.
 66. A method of claim 64wherein the polymer is polygalacturonic acid having a weight averagemolecular weight of less than 30,000 in an amount between about 5 andabout 10 grams/liter, the contrast agent is Mn(II) in an amount betweenabout 20 and about 70 milligrams/liter, the suspending agent is xanthangum in an amount between about 0.5 and about 3.0 grams/liter, theosmotically active material is glycine in an amount between about 2 andabout 6 grams/liter, and the pH regulating additive is effective tomaintain the pH between about 5 and about 8 and is a combination ofsodium bicarbonate in an amount between about 2 and about 6 grams/literand sodium acetate buffer in an amount between about 2 and about 6grams/liter, and wherein the contrast medium has an osmolarity ofbetween about 250 and about 260 milliosmoles/liter.
 67. A method fordiagnosing the presence of diseased tissue in a patient comprising (i)administering to the patient a diagnostically effective amount of acontrast medium comprising an aqueous solution or suspension of abiocompatible polymer in admixture with a contrast agent bound to acomplexing agent, wherein the contrast medium is hypoosmotic to bodilyfluids of the patient, and (ii) scanning the patient using magneticresonance imaging to obtain visible images of any diseased tissue in thepatient.
 68. A method of claim 67 wherein the scanning is of thegastrointestinal region of the patient.
 69. A method of claim 67 whereinthe scanning is of the vasculature of the patient.
 70. A method of claim67 wherein said hypoosmotic contrast medium has an osmolarity of lessthan 280 milliosmoles/liter.
 71. A method of claim 70 wherein saidosmolarity is between about 200 and about 270 milliosmoles/liter.
 72. Amethod of claim 71 wherein said osmolarity is between about 220 andabout 260 milliosmoles/liter.
 73. A method of claim 72 wherein saidosmolaritg is between about 250 and about 260 milliosmoles/liter.
 74. Amethod of claim 67 wherein the polymer is a natural polymer.
 75. Amethod of claim 67 wherein the polymer is a synthetic polymer.
 76. Amethod of claim 67 wherein the polymer is a polysaccharide.
 77. A methodof claim 67 wherein the polymer is a polyuronic acid.
 78. A method ofclaim 67 wherein the polymer has a weight average molecular weight ofless than 30,000.
 79. A method of claim 67 wherein the polymer is apolysaccharide selected from the group consisting of arabinans,fructans, fucans, galactans, galacturonans, glucans, mannans, xylans,levan, fucoidan, carrageenan, galactocarolose, pectin, pectic acid,amylose, pullulan, glycogen, amylopectin, cellulose,carboxylmethylcellulose, hydroxypropylmethylcellulose, dextran,pustulan, chitin, agarose, keratan, chondroitin, dermatan, hyaluronicacid, alginic acid, and polysaccharides containing at least one aldose,ketose, acid or amine selected from the group consisting of erythrose,threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose,mannose, gulose, idose, galactose, talose, erythrulose, ribulose,xylulose, psicose, fructose, sorbose, tagatose, glucuronic acid,gluconic acid, glucaric acid, galacturonic acid, mannuronic acid,glucosamine, galactosamine and neuraminic acid.
 80. A method of claim 67wherein the polymer is selected from the group consisting ofpolyethylenes, polyoxyethylenes, polypropylenes, pluronic acids,pluronic alcohols, polyvinyls, and polyvinylpyrrolidones.
 81. A methodof claim 67 wherein the polymer is polygalacturonic acid.
 82. A methodof claim 67 wherein the polymer is polyethylene glycol.
 83. A method ofclaim 67 wherein the contrast agent is selected from the groupconsisting of paramagnetic, superparamagnetic and proton densitycontrast agents.
 84. A method of claim 83 wherein the contrast agent isa paramagnetic contrast agent which is a transition, lanthanide oractinide element.
 85. A method of claim 84 wherein the paramagneticcontrast agent is selected from the group consisting of Gd(III), Mn(II),Cu(II), Cr(III), Fe(II), Fe(III), Co(II), Er(II), Ni(II), Eu(III) andDy(III).
 86. A method of claim 85 wherein the paramagnetic contrastagent is Mn(II).
 87. A method of claim 67 further comprising asuspending agent.
 88. A method of claim 87 wherein the suspending agentis selected from the group consisting of xanthum gum, acacia, agar,alginic acid, aluminum monostearate, bassorin, karaya, gum arabic,unpurified bentonite, purified bentonite, bentonite magma, calciumcarboxymethylcellulose, sodium carboxymethylcellulose, carrageenan,microcrystalline cellulose, dextran, gelatin, guar gum,hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, magnesium aluminum silicate,methylcellulose, pectin, casein, gelatin, polyethylene oxide, polyvinylalcohol, povidone, propylene glycol, alginate, silicon dioxide, silicondioxide colloidal, alginate, sodium alginate, and tragacanth.
 89. Amethod of claim 88 wherein the suspending agent is xanthan gum.
 90. Amethod of claim 67 further comprising an osmotically active material.91. A method of claim 90 wherein the osmotically active material isselected from the group consisting of erythrose, threose, ribose,arabinose, xylose, lyxose, allose, altrose, glucose, mannose, idose,galactose, talose, ribulose, fructose, sorbitol, mannitol,sedoheptulose, lactose, sucrose, maltose, cellobiose, glycine, serine,threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid,glutamic acid, lysine, arginine, histidine, propylene glycol,polypropylene glycol, ethylene glycol, polyethylene glycol andpolyvinylpyrrolidone.
 92. A method of claim 91 wherein the osmoticallyactive material is glycine.
 93. A method of claim 67 further comprisinga pH regulating additive effective to maintain a pH of between about 3and about
 10. 94. A method of claim 93 wherein the pH regulatingadditive is effective to maintain a pH of between about 3 and
 8. 95. Amethod of claim 67 further comprising a biocompatible gas.
 96. A methodof claim 95 wherein the biocompatible gas is selected from the groupconsisting of air, oxygen, carbon dioxide, nitrogen, xenon, neon andargon.
 97. A method of claim 67 further comprising a suspending agent,an osmotically active material, and a pH regulating additive effectiveto maintain a pH of between about 3 and about
 10. 98. A method of claim97 wherein the polymer is polygalacturonic acid having a weight averagemolecular weight of less than 30,000, the contrast agent is Mn(II), thesuspending agent is xanthan gum, the osmotically active material isglycine, and the pH regulating additive is selected from the groupconsisting of sodium bicarbonate, glacial acetic acid and sodium acetatebuffer, and wherein the contrast medium has an osmolarity of betweenabout 200 and about 270 milliosmoles/liter.
 99. A method of claim 97wherein the polymer is polygalacturonic acid having a weight averagemolecular weight of less than 30,000 in an amount between about 5 andabout 10 grams/liter, the contrast agent is Mn(II) in an amount betweenabout 20 and about 70 milligrams/liter, the suspending agent is xanthangum in an amount between about 0.5 and about 3.0 grams/liter, theosmotically active material is glycine in an amount between about 2 andabout 6 grams/liter, and the pH regulating additive is effective tomaintain the pH between about 5 and about 8 and is a combination ofsodium bicarbonate in an amount between about 2 and about 6 grams/literand sodium acetate buffer in an amount between about 2 and about 6grams/liter, and wherein the contrast medium has an osmolarity ofbetween about 250 and about 260 milliosmoles/liter.
 100. A contrastmedium for magnetic resonance imaging comprising an aqueous solution orsuspension of a biocompatible synthetic polymer in admixture with acontrast agent bound to a complexing agent.
 101. A method of providingan image of an internal region of a patient comprising (i) administeringto the patient a diagnostically effective amount of a contrast mediumcomprising an aqueous solution or suspension of a biocompatiblesynthetic polymer in admixture with a contrast agent bound to acomplexing agent, and (ii) scanning the patient using magnetic resonanceimaging to obtain visible images of the region.
 102. A method of claim101 wherein the region is the gastrointestinal region.
 103. A method fordiagnosing the presence of diseased tissue in a patient comprising (i)administering to the patient a diagnostically effective amount of acontrast medium comprising an aqueous solution or suspension of abiocompatible synthetic polymer in admixture with a contrast agent boundto a complexing agent, and (ii) scanning the patient using magneticresonance imaging to obtain visible images of any diseased tissue in thepatient.
 104. A method of claim 103 wherein the scanning is of thegastrointestinal region of the patient.
 105. A contrast medium formagnetic resonance imaging comprising an aqueous solution or suspensionof a bicompatible polymer selected from the group consisting ofpolygalacturonic acid, polyglucuronic acid, polymannuronic acid andhyaluronic acid, in admixture with a contrast agent bound to acomplexing agent.
 106. A contrast medium of claim 105 wherein thepolymer is polygalacturonic acid.
 107. A contrast medium of claim 106wherein the contrast agent is selected from the group consisting ofparamagnetic, superparamagnetic, and proton density contrast agents.108. A contrast medium of claim 107 wherein the contrast agent is aparamagnetic agent.
 109. A contrast medium of claim 108 wherein theparamagnetic agent is Mn(II).
 110. A method of providing an image of aninternal region of a patient comprising (i) administering to the patienta diagnostically effective amount of a contrast medium comprising anaqueous solution or suspension of a biocompatible polymer selected fromthe group consisting of polygalacturonic acid, polyglucuronic acid,polymannuronic acid, and hyaluronic acid, in admixture with a contrastagent bound to a complexing agent, and (ii) scanning the patient usingmagnetic resonance imaging to obtain visible images of the region. 111.A method of claim 110 wherein the region is the gastrointestinal region.112. A method of claim 110 wherein the polymer is polygalacturonic acid.113. A method of claim 112 wherein the contrast agent is selected fromthe group consisting of paramagnetic, superparamagnetic, and proteindensity contrast agents.
 114. A method of claim 113 wherein the contrastagent is a paramagnetic agent.
 115. A method of claim 114 wherein theparamagnetic agent is Mn(II).
 116. A method for diagnosing the presenceof diseased tissue in a patient comprising (i) administering to thepatient a diagnostically effective amount of a contrast mediumcomprising an aqueous solution or suspension of a biocompatible polymerselected from the group consisting of polygalacturonic acid,polyglucuronic acid, polymannuronic acid, and hyaluronic acid, inadmixture with a contrast agent bound to a complexing agent, and (ii)scanning the patient using magnetic resonance imaging to obtain visibleimages of any diseased tissue in the patient.
 117. A method of claim 116wherein the scanning is of the gastrointestinal region of the patient.118. A method of claim 116 wherein the polymer is polygalacturonic acid.119. A method of claim 118 wherein the contrast agent is selected fromthe group consisting of paramagnetic, superparamagnetic, and proteindensity contrast agents.
 120. A method of claim 119 wherein the contrastagent is a paramagnetic agent.
 121. A method of claim 120 wherein theparamagnetic agent is Mn(II).
 122. A contrast medium of claim 1 whereinthe polymer is polygalacturonic acid having a weight average molecularweight of less than about 30,000.
 123. A contrast medium of claim 122wherein the contrast agent is Mn(II).
 124. A method of claim 34 whereinthe polymer is polygalacturonic acid having a weight average molecularweight of less than about 30,000.
 125. A method of claim 124 wherein thecontrast agent is Mn (II).
 126. A method of claim 67 wherein the polymeris polygalacturonic acid having a weight average molecular weight ofless than about 30,000.
 127. A method of claim 126 wherein the contrastagent is Mn(II) .
 128. A contrast medium of claim 105 wherein thepolymer is polygalacturonic acid having a weight average molecularweight of less than about 30,000.
 129. A contrast medium of claim 128wherein the contrast agent is Mn(II).
 130. A method of claim 110 whereinthe polymer is polygalacturonic acid having a weight average molecularweight of less than about 30,000.
 131. A method of claim 130 wherein thecontrast agent is Mn(II) .
 132. A method of claim 116 wherein thepolymer is polygalacturonic acid having a weight average molecularweight of less than about 30,000.
 133. A method of claim 132 wherein thecontrast agent is Mn(II).
 134. A contrast medium of claim 1 wherein thecomplexing agent is selected from the group consistingof:diethylenetriaminepentaacetic acid; ethylenediaminetetraacetic acid;1,4,7,10-tetraazacyclododecane-N,N',N',N'"-tetraacetic acid;1,4,7,10-tetraazacyclododecane-N,N',N"-triacetic acid;3,6,9-triaza-12-oxa-3,6,9-tricarboxymethylene-10-carboxy-13-phenyltridecanoicacid; hydroxybenzylethylenediamine diacetic acid;N,N'-bis(pyridoxyl-5-phosphate)ethylene diamine; N,N'-diacetate;1,4,7-triazacyclononane-N,N',N"-triacetic acid;1,4,8,11-tetraazacyclotetradecane-N,N'N",N'"-tetraacetic acid; andkryptands.
 135. A contrast medium of claim 134 wherein the complexingagent is diethylenetriaminepentaacetic acid.
 136. A method of claim 34wherein the complexing agent is selected from the group consistingof:diethylenetriaminepentaacetic acid; ethylenediaminetetraacetic acid;1,4,7,10-tetraazacyclododecane-N,N',N',N'"-tetraacetic acid;1,4,7,10-tetraazacyclododecane-N,N',N"-triacetic acid;3,6,9-triaza-12-oxa-3,6,9-tricarboxymethylene-10-carboxy-13-phenyltridecanoicacid; hydroxybenzylethylenediamine diacetic acid;N,N'-bis(pyridoxyl-5-phosphate)ethylene diamine; N,N'-diacetate;1,4,7-triazacyclononane-N,N',N"-triacetic acid;1,4,8,11-tetraazacyclotetradecane-N,N'N",N'"-tetraacetic acid; andkryptands.
 137. A contrast medium of claim 136 wherein the complexingagent is diethylenetriaminepentaacetic acid.
 138. A method of claim 67wherein the complexing agent is selected from the group consistingof:diethylenetriaminetetraacetic acid; ethylenediaminetetraacetic acid;1,4,7,10-tetraazacyctododecane-N,N',N',N'"-tetraacetic acid;1,4,7,10-tetraazacyctododecane-N,N',N"-triacetic acid;3,6,9-triaza-12-oxa-3,6,9-tricarboxymethylene-10-carboxy-13-phenyltridecanoicacid; hydroxybenzylethylenediamine diacetic acid;N,N'-bis(pyridoxyl-5-phosphate)ethylene diamine; N,N'-diacetate;1,4,7-triazacyclononane-N,N',N"-triacetic acid;1,4,8,11-tetraazacyclotetradecane-N,N'N",N'"-tetraacetic acid; andkryptands.
 139. A contrast medium of claim 138 wherein the complexingagent is diethylenetriaminepentaacetic acid.
 140. A contrast medium ofclaim 100 wherein the complexing agent is selected from the groupconsisting of:diethylenetriaminepentaacetic acid;ethylenediaminetetraacetic acid;1,4,7,10-tetraazacyclododecane-N,N',N',N'"-tetraacetic acid;1,4,7,10-tetraazacyclododecane-N,N',N"-triacetic acid;3,6,9-triaza-12-oxa-3,6,9-tricarboxymethylene-10-carboxy-13-phenyltridecanoicacid; hydroxybenzylethylenediamine diacetic acid;N,N'-bis(pyridoxyl-5-phosphate)ethylene diamine; N,N'-diacetate;1,4,7-triazacyclononane-N,N',N"-triacetic acid;1,4,8,11-tetraazacyclotetradecane-N,N'N",N'"-tetraacetic acid; andkryptands.
 141. A contrast medium of claim 140 wherein the complexingagent is diethylenetriaminepentaacetic acid.
 142. A method of claim 101wherein the complexing agent is selected from the group consistingof:diethylenetriaminepentaacetic acid; ethylenediaminetetraacetic acid;1,4,7,10-tetraazacyclododecane-N,N',N',N'"-tetraacetic acid;1,4,7,10-tetraazacyclododecane-N,N',N"-triacetic acid;3,6,9-triaza-12-oxa-3,6,9-tricarboxymethylene-10-carboxy-13-phenyltridecanoicacid; hydroxybenzylethylenediamine diacetic acid;N,N'-bis(pyridoxyl-5-phosphate)ethylene diamine; N,N'-diacetate;1,4,7-triazacyclononane-N,N',N"-triacetic acid;1,4,8,11-tetraazacyclotetradecane-N,N'N",N'"-tetraacetic acid; andkryptands.
 143. A contrast medium of claim 142 wherein the complexingagent is diethylenetriaminepentaacetic acid.
 144. A method of claim 103wherein the complexing agent is selected from the group consistingof:diethylenetriaminepentaacetic acid; ethylenediaminetetraacetic acid;1,4,7,10-tetraazacyclododecane-N,N',N',N'"-tetraacetic acid;1,4,7,10-tetraazacyclododecane-N,N',N"-triacetic acid;3,6,9-triaza-12-oxa-3,6,9-tricarboxymethylene-10-carboxy-13-phenyltridecanoicacid; hydroxybenzylethylenediamine diacetic acid;N,N'-bis(pyridoxyl-5-phosphate)ethylene diamine; N,N'-diacetate;1,4,7-triazacyclononane-N,N',N"-triacetic acid;1,4,8,11-tetraazacyclotetradecane-N,N'N",N'"-tetraacetic acid; andkryptands.
 145. A contrast medium of claim 144 wherein the complexingagent is diethylenetriaminepentaacetic acid.
 146. A contrast medium ofclaim 105 wherein the complexing agent is selected from the groupconsisting of:diethylenetriaminepentaacetic acid;ethylenediaminetetraacetic acid;1,4,7,10-tetraazacyclododecane-N,N',N',N'"-tetraacetic acid;1,4,7,10-tetraazacyclododecane-N,N',N"-triacetic acid;3,6,9-triaza-12-oxa-3,6,9-tricarboxymethylene-10-carboxy-13-phenyltridecanoicacid; hydroxybenzylethylenediamine diacetic acid;N,N'-bis(pyridoxyl-5-phosphate)ethylene diamine; N,N'-diacetate;1,4,7-triazacyclononane-N,N',N"-triacetic acid;1,4,8,11-tetraazacyclotetradecane-N,N'N",N'"-tetraacetic acid; andkryptands.
 147. A contrast medium of claim 146 wherein the complexingagent is diethylenetriaminepentaacetic acid.
 148. A method of claim 110wherein the complexing agent is selected from the group consistingof:diethylenetriaminepentaacetic acid; ethylenediaminetetraacetic acid;1,4,7,10-tetraazacyclododecane-N,N',N',N'"-tetraacetic acid;1,4,7,10-tetraazacyclododecane-N,N',N"-triacetic acid;3,6,9-triaza-12-oxa-3,6,9-tricarboxymethylene-10-carboxy-13-phenyltridecanoicacid; hydroxybenzylethylenediamine diacetic acid;N,N'-bis(pyridoxyl-5-phosphate)ethylene diamine; N,N'-diacetate;1,4,7-triazacyclononane-N,N',N"-triacetic acid;1,4,8,11-tetraazacyclotetradecane-N,N',N",N'"-tetraacetic acid; andkryptands.
 149. A contrast medium of claim 148 wherein the complexingagent is diethylenetriaminepentaacetic acid.
 150. A method of claim 116wherein the complexing agent is selected from the group consistingof:diethylenetriaminepentaacetic acid; ethylenediaminetetraacetic acid;1,4,7,10-tetraazacyclododecane-N,N',N',N'"-tetraacetic acid;1,4,7,10-tetraazacyclododecane-N,N',N"-triacetic acid;3,6,9-triaza-12-oxa-3,6,9-tricarboxymethylene-10-carboxy-13-phenyltridecanoicacid; hydroxybenzylethylenediamine diacetic acid;N,N'-bis(pyridoxyl-5-phosphate)ethylene diamine; N,N'-diacetate;1,4,7-triazacyclononane-N,N',N"-triacetic acid;1,4,8,11-tetraazacyclotetradecane-N,N'N",N'"-tetraacetic acid; andkryptands.
 151. A contrast medium of claim 150 wherein the complexingagent is diethylenetriaminepentaacetic acid.
 152. A contrast medium ofclaim 123 wherein the complexing agent is diethylenetriaminepentaaceticacid.
 153. A contrast medium of claim 125 wherein the complexing agentis diethylenetriaminepentaacetic acid.
 154. A contrast medium of claim127 wherein the complexing agent is diethylenetriaminepentaacetic acid.155. A contrast medium of claim 129 wherein the complexing agent isdiethylenetriaminepentaacetic acid.
 156. A contrast medium of claim 131wherein the complexing agent is diethylenetriaminepentaacetic acid. 157.A contrast medium of claim 133 wherein the complexing agent isdiethylenetriaminepentaacetic acid.